TY - JOUR
T1 - Cytotoxicity of 11-epi-sinulariolide acetate isolated from cultured soft corals on HA22T cells through the endoplasmic reticulum stress pathway and mitochondrial dysfunction
AU - Lin, Jen Jie
AU - Wang, Robert Y.L.
AU - Chen, Jiing Chuan
AU - Chiu, Chien Chih
AU - Liao, Ming Hui
AU - Wu, Yu Jen
N1 - Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2016/11
Y1 - 2016/11
N2 - Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress responseand protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulatedexpression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer bindingprotein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated withgrowth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK)-activating transcription factor (ATF) 6-CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal kinase (JNK)-cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxiceffects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways.
AB - Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress responseand protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulatedexpression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer bindingprotein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated withgrowth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK)-activating transcription factor (ATF) 6-CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal kinase (JNK)-cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxiceffects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways.
KW - 11-epi-sinulariolide acetate
KW - Antitumor
KW - ER stress
KW - Hepatocellular carcinoma
KW - Mitochondrial dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85016293430&partnerID=8YFLogxK
U2 - 10.3390/ijms17111787
DO - 10.3390/ijms17111787
M3 - 文章
C2 - 27801783
AN - SCOPUS:85016293430
SN - 1661-6596
VL - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 11
M1 - 1787
ER -